This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The nature and importance of the HIV protease target is well known. The problem of the evolution of drug resistance is now recognized as a major impediment to effective long-term therapeutic treatment. Novel synthetic approaches, guided by computational docking hold the promise of generating more effective HIV protease inhibitors, that are robust in the face of resistance. The possibilities of in situ synthesis of inhibitors utilizing "click chemistry" in the context of protease mutants points to a new flexible approach to this problem.